Cerebral ischemia, or lack of blood in the brain, results from a number of clinical conditions. For instance, stroke involves blockade of one or more of the arteries in the brain; head injuries obstruct blood flow to undamaged parts of the brain; cardiac arrest or circulatory shock deprive adequate blood supply to the brain and spinal cord; brain tumor could reduce passage of blood in cerebral vessels. The consequence of cerebral ischemia is most serious. Due to the great demand for oxygen and glucose by brain cells for warm-blooded animals, neurons lose their functions after seconds of complete ischemia. Damage becomes irreversible when ischemia is sustained for several minutes. Dependent on the area of the brain involved, death or long-term disability can be expected from cerebral ischemia.
Models for measuring cerebral ischemia in laboratory animals are used for the studies of the pathophysiology and experimental drug therapy. Occlusion of both common carotid arteries for sufficiently long periods of time produce death in the Mongolian gerbils and rats of the Fischer 344 strain. Similar carotid occlusion for five minutes under halothane anesthesia in the gerbils produce no death but a delayed cell loss in a specific area of the hippocampus of the brain. There was also a characteristic behavioral change in the post-ischemic gerbils marked by hyper-activity and perseveration in locomotion. Death, cell damage and behavioral and cognitive impairment from cerebral ischemia all have direct clinical parallel and have predictive value in evaluation of drug treatment.
The discovery that naloxone, a specific narcotic antagonist, had beneficial effects on circulatory shocks suggested to many investigators that the endogenous opiate systems may be involved in the pathophysiology of the cardiovascular system (review by Holaday, 1983). In the study of naloxone on spinal shock in cats, Faden et al. (1981) reported that naloxone produced a pressor response and improved spinal cord perfusion following spinal cord injury. In addition, the naloxone-treated cats had a smaller degree of long-term neurologic impairment compared to the saline-treated controls. The findings were confirmed by Young et al. (1981). A potential therapeutic use of naloxone in stroke was suggested by the study of Baskin et al. (1982) where baboons were rendered hemiplegic through selected occlusion of cerebral arteries. Naloxone treatment reduced the neurologic deficits, apparently independent of systemic circulatory effects. Subsequent studies with naloxone on the Mongolian gerbil models of cerebral ischemia led to discrepant findings. Whereas Hosobuchi et al. (1982) used unilateral carotid occlusion in the gerbils and found naxolone to reduce the post-ischemic neurologic deficit, Holaday and D'Amato (1982) failed to find any beneficial effect with naloxone using both unilateral and bilateral carotid occlusions. Both groups of investigators, however, did find morphine to exacerbate the post-stroke deficits. There is, at this time no specific and effective treatment for cerebral ischemia and cerebral edema resulting from the various causes. This invention provides a new course of treatment for this type of medical condition. References:
Baskin, D. S., Kieck, C. F. and Hosobuchi, Y.: Life Science, 31:2201, 1982.
Faden, A. L., Jacobs, T. P. and Holaday, J. W.: Science, 211:493, 1981.
Holaday, J. W.: Biochemical Pharmacology, 32:573, 1983.
Holaday, J. W. and D'Amato, R. J., Life Science, 31:385, 1982.
Hosobuchi, Y., Baskin, D. S. and Woo, S. K., Science, 215:69, 1982.
Young, W., Flamm, E. S., Demopoulos, H. G., Tomasula, J. H. and DeCrescito, V., J. of Neurosurgery, 55:209, 1981.